Process for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives, polymorphs and pseudomorphs thereof

ABSTRACT

The present invention is related to novel processes for preparing anhydrous and hydrated forms of piperidine derivatives, polymorphs and pseudomorphs thereof of the formulas  
                 
 
     which are useful as antihistamines, antiallergic agents and bronchodilators.

[0001] This is a Continuation-In-Part Application of patent applicationSer. No. 08/245,731, filed May 18, 1994.

[0002] The present invention is related to novel processes for preparinganhydrous and hydrated forms of piperidine derivatives, polymorphs andpseudomorphs thereof which are useful as antihistamines, antiallergicagents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S.Pat. No. 4,254,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958, Apr. 25,1981].

SUMMARY OF THE INVENTION

[0003] The present invention provides a process for preparing anhydrous,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formulas

[0004] wherein

[0005] R₁ represents hydrogen or hydroxy;

[0006] R₂ represents hydrogen; or

[0007] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0008] n is an integer of from 1 to 5;

[0009] R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched;

[0010] each of A is hydrogen or hydroxy; and

[0011] pharmaceutically acceptable salts and individual optical isomersthereof,

[0012] comprising subjecting the corresponding hydrated,pharmaceutically acceptable acid addition salt to an azeotropicdistillation.

[0013] In addition, the present invention also provides a process forpreparing anhydrous, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula

[0014] wherein

[0015] R₁ represents hydrogen or hydroxy;

[0016] R₂ represents hydrogen; or

[0017] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0018] n is an integer of from 1 to 5;

[0019] R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched;

[0020] each of A is hydrogen or hydroxy; and

[0021] pharmaceutically acceptable salts and individual optical isomersthereof,

[0022] comprising subjecting the corresponding hydrated,pharmaceutically acceptable acid addition salt to a water-minimizingrecrystallization.

[0023] In addition, the present invention provides a process forpreparing the hydrated, pharmaceutically acceptable acid addition saltsof piperidine derivatives of the formula

[0024] wherein

[0025] R₁ represents hydrogen or hydroxy;

[0026] R₂ represents hydrogen; or

[0027] R₁ and R₂ taken together form a second bond between the carbonatoms bearing R₁ and R₂;

[0028] n is an integer of from 1 to 5;

[0029] R₃ is —CH₂OH, —COOH or —COOalkyl wherein the alkyl moiety hasfrom 1 to 6 carbon atoms and is straight or branched;

[0030] each of A is hydrogen or hydroxy; and

[0031] pharmaceutically acceptable salts and individual optical isomersthereof,

[0032] comprising subjecting the corresponding anhydrous,pharmaceutically acceptable acid addition salts to an aqueousrecrystallization.

[0033] In addition, the present invention provides processes forpreparing polymorphs of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride designated herein as Form Iand Form III and processes for preparing psuedomorphs of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride designated herein as Form IIand Form IV.

[0034] The Form I polymorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 196-201° C.; a melt endotherm with extrapolated onset in the rangeof about 195-199° C. as determined by differential scanning calorimetry;and an X-ray powder diffraction pattern essentially as shown in Table 1wherein the XRPD patterns were measured using a powder diffractometerequipped with a Co X-ray tube source. The sample was illuminated withCo₁ radiation and XRPD data were collected from 5 to 55° 2. (intensitiesmay vary radically due to preferred orientation). TABLE 1 D-Space,Angstroms Intensity, I/I_(o), % 11.8  30 7.3 30 6.3 65 5.9 35 5.0 45 4.8100  4.4 45 3.9 60 3.8 75 3.7 30

[0035] The Form III polymorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 166-171° C.; a broad endotherm below about 90° C., a meltendotherm with an extrapolated onset of about 166° C. as determined bydifferential scanning calorimetry; and an X-ray powder diffractionpattern essentially as shown in Table 2 wherein the XRPD patterns weremeasured using a powder diffractometer equipped with a Co X-ray tubesource. The sample was illuminated with Co₁ radiation and XRPD data werecollected from 5 to 55° 2. (intensities may vary radically due topreferred orientation). TABLE 2 D-Space, Angstroms Intensity, I/I_(o), %9.0 95 4.9 100  4.8 35 4.6 25 4.5 25 3.7 25

[0036] The Form II pseudomorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 100-105° C.; a large broad endotherm below about 100° C. and asmall endothermic peak (about 2 joules/gram) with extrapolated onsets inthe range of about 124-126° C. as determined by differential scanningcalorimetry; and an X-ray powder diffraction pattern essentially asshown in Table 3 wherein the XRPD patterns were measured using a powderdiffractometer equipped with a Co X-ray tube source. The sample wasilluminated with Co₁ radiation and XRPD data were collected from 5 to55° 2. (intensities may vary radically due to preferred orientation).TABLE 3 D-Space, Angstroms Intensity, I/I_(o), % 7.8 45 6.4 44 5.2 854.9 60 4.7 80 4.4 55 4.2 50 4.1 60 3.7 75 3.6 60 3.5 50

[0037] The Form IV pseudomorph may be identified by the followingcharacteristics: a visual melting point (capillary tube) in the range ofabout 113-118° C.; two broad overlapping endotherms below about 100° C.and an additional endotherm with an extrapolated onset at approximately146° C. as determined by differential scanning calorimetry and an X-raypowder diffraction pattern essentially as shown in Table 4 wherein theXRPD patterns were measured using a powder diffractometer equipped witha Co X-ray tube source. The sample was illuminated with Co₁ radiationand XRPD data were collected from 5 to 55° 2. (intensities may varyradically due to preferred orientation). TABLE 4 D-Space, AngstromsIntensity, I/I_(o), % 10.4  60 7.0 45 6.4 50 5.3 100  5.2 55 4.3 75 4.150 4.0 45 3.8 60 3.5 55

DETAILED DESCRIPTION OF THE INVENTION

[0038] Pharmaceutically acceptable acid addition salts of the compoundsof formula (I) and (II), both anhydrous and hydrated, are those of anysuitable inorganic or organic acid. Suitable inorganic acids are, forexample, hydrochloric, hydrobromic, sulfuric, and phosphoric acids.Suitable organic acids include carboxylic acids, such as, acetic,propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic,tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, anddihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids,such as, methanesulfonic, ethanesulfonic and hydroxyethanesulfonic acid.

[0039] As used herein, the term “hydrate” refers to a combination ofwater with a compound of formula (I) or (II) wherein the water retainsits molecular state as water and is either absorbed, adsorbed orcontained within a crystal lattice of the substrate molecule of formula(I) or (II).

[0040] As used herein, the term “adsorped” refers to the physical statewherein the water molecule in the hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) is distributed over the surface of the solid hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II).

[0041] As used herein, the term “absorbed” refers to the physical statewherein the water molecule in the hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) is distributed throughout the body of the solid hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II).

[0042] Hydrated, pharmaceutically acceptable acid addition salts of thecompounds of formula (I) and (II) are those hydrates ranging fromessentially 0.10 to 5 molecules of water per molecule of substrate saltof formula (I) or (II).

[0043] As used herein, the term “azeotropic mixture” refers to a liquidmixture of two or more substances which behaves like a single substancein that the vapor produced by partial evaporation of liquid has the samecomposition as the liquid. The constant boiling mixture exhibits eithera maximum or minimum boiling point as compared with that of othermixtures of the same substance.

[0044] As used herein, the term “azeotropic distillation” refers to atype of distillation in which a substance is added to the mixture to beseparated in order to form an azeotropic mixture with one or more of theconstituents of the original mixture. The azeotrope or azeotropes thusformed will have boiling points different from the boiling points of theoriginal mixture. As used herein, the term “azeotropic distillation”also refers to co-distillation.

[0045] As used herein, the term “water-minimizing recrystallization”refers to a recrystallization wherein the ratio of anhydrous solvent tosubstrate hydrate is such that the percentage of water present isminimized, thereby inducing precipitation of the anhydrous form of thesubstrate.

[0046] As used herein, the term “aqueous recrystallization” refers tothose processes wherein either 1) a solid material is dissolved in avolume of water or a water/organic solvent mixture sufficient to causedissolution and the solid material recovered by evaporation of thesolvent; 2) a solid material is treated with a minimal amount of wateror a water/organic solvent mixture which is not sufficient to causedissolution, heated to obtain dissolution and cooled to inducecrystallization or 3) a solid material is dissolved in a volume of wateror a water/organic solvent mixture sufficient to cause dissolution andthen the solvent is partially evaporated to form a saturated solutionwhich induces crystallization.

[0047] As used herein, the term “crystal digestion” refers to thatprocess wherein a solid material is treated with a minimal amount ofwater or water/organic solvent mixture which is not sufficient to causedissolution and either heating or stirring at ambient temperature untilthe desired transformation has taken place.

[0048] As used herein, the term “antisolvent” refers to a poor solventfor the substance in question which when added to a solution of thesubstance, causes the substance to precipitate.

[0049] As used herein, the term “suitable temperature” refers to thattemperature which is sufficient to cause dissolution and to permit theprecipitation of the desired substance either upon addition of anantisolvent or upon removal of the co-solvent by azeotropicdistillation.

[0050] The anhydrous, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula (I) and (II) may be prepared fromthe corresponding hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II) bysubjecting the corresponding hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) toan azeotropic distillation.

[0051] For example, the appropriate hydrated, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II) is first dissolved in a volume of a suitable solvent orsolvent mixture which is sufficient to cause dissolution. Examples ofsuch solvents are water, C₁-C₅ alkanols such as methanol, ethanol andthe like; ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like andaqueous mixtures of these solvents, such as acetone/water, methyl ethylketone/water, water/acetone and water/acetone/ethyl acetate. Anadditional volume of the same solvent used to effect dissolution orsecond suitable anhydrous antisolvent is then added to this solution,which is then heated to a boiling point which is suitable toazeotropically remove water and other low boiling components. Suitableanhydrous antisolvents for use in the azeotropic distillation are, forexample, ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like; C5-C8aliphatic solvents such as pentane, hexane and the like; aliphaticnitrites, such as acetonitrile and mixtures of these solvents such asacetone/ethyl acetate and the like. The azeotropic mixture of water andsolvent is removed by distillation until the temperature changes,indicating that the azeotropic mixture is completely removed. Thereaction mixture is cooled and the corresponding anhydrous,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) and (II) is recovered from the reactionzone by, for example filtration.

[0052] In addition, the anhydrous, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) maybe prepared from the corresponding hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) and(II) by subjecting the corresponding hydrated, pharmaceuticallyacceptable acid addition salts of piperidine derivatives of the formula(I) and (II) to a water-minimizing recrystallization.

[0053] For example, the appropriate hydrated, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II) is dissolved in a volume of a suitable anhydrous solvent orsolvent mixture which is sufficient to cause dissolution and heated toreflux. Examples of such solvents are water, C₁-C₅ alkanols such asmethanol, ethanol and the like; ketone solvents such as acetone, methylethyl ketone and the like; aliphatic ester solvents such as ethylacetate, methyl acetate, methyl formate, ethyl formate, isopropylacetate and the like and aqueous mixtures of these solvents, such asacetone/water, methyl ethyl ketone/water, water/acetone andwater/acetone/ethyl acetate. An additional volume of the same solventused to effect dissolution or second suitable anhydrous antisolvent isthen added in a quantity sufficient to initiate precipitation of theanhydrous, pharmaceutically acceptable acid addition salt of piperidinederivatives of the formula (I) and (II). Suitable anhydrous antisolventsare, for example, ketone solvents such as acetone, methyl ethyl ketoneand the like; aliphatic ester solvents such as ethyl acetate, methylacetate, methyl formate, ethyl formate, isopropyl acetate and the like;mixtures of ketone solvents and aliphatic ester solvents such asacetone/ethyl acetate and the like; C₅-C₈ aliphatic solvents such aspentane, hexane and the like; aliphatic nitrites, such as acetonitrileand mixtures of these solvents such as acetone/ethyl acetate and thelike as well as mixtures of water and ketone solvents such asacetone/water and the like; and mixtures of water, ketone solvents andaliphatic ester solvents such as acetone/water/ethyl acetate. Thereaction mixture is cooled and the corresponding anhydrous,pharmaceutically acceptable acid addition salt of piperidine derivativesof the formula (I) and (II) is recovered from the reaction zone by, forexample filtration.

[0054] Polymorphic forms of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Forms I and III) may beprepared by a variety of methods as detailed below.

[0055] Form III to Form I

[0056] For example, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) may be prepared fromanhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form III), by subjecting theanhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form III) to a crystaldigestion as described above.

[0057] Form II to Form III

[0058] In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form III) may be preparedfrom hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II), by subjecting thehydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II) to water-minimizingrecrystallization as described above.

[0059] Form II to Form I

[0060] In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) may be prepared fromhydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II), by subjecting thehydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II) to water-minimizingrecrystallization as described above or by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II) to an azeotropicdistillation.

[0061] Form IV to Form I

[0062] In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) may be prepared fromhydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form IV), by subjecting thehydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form IV) to water-minimizingrecrystallization or to an azeotropic distillation as described above.

[0063] The hydrated, pharmaceutically acceptable acid addition salts ofpiperidine derivatives of the formula (I) may be prepared from thecorresponding compound of the formula (II) wherein R₃ is —COOalkyl bysubjecting the corresponding compound of the formula (II) wherein R₃ is—COOalkyl to a reduction using an appropriate reducing agent, such assodium borohydride, potassium borohydride, sodium cyanoborohydride, ortetramethylammonium borohydride in a suitable solvent, such as,methanol, ethanol, isopropyl alcohol or n-butanol, aqeuous mixturesthereof or basic solutions thereof, at temperatures ranging from about0° C. to the reflux temperature of the solvent, and the reaction timevaries from about ½ hour to 8 hours. After quenching and acidifying withan suitable acid, such as hydrochloric acid, the hydrated,pharmaceutically acceptable acid addition salts of piperidinederivatives of the formula (I) are recovered from the reaction zone bycrystallization and filtration.

[0064] In addition, the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II) maybe prepared from the corresponding anhydrous, pharmaceuticallyacceptable acid addition salts of the formula (I) and (II) by subjectingthe corresponding anhydrous, pharmaceutically acceptable acid additionsalts of formula (I) and (II) to an aqueous recrystallization.

[0065] For example, the appropriate anhydrous, pharmaceuticallyacceptable acid addition salt of piperidine derivatives of the formula(I) and (II) is treated with a minimal volume of water or suitablewater/organic solvent mixture which is insufficient to cause dissolutionand heated to reflux. The reaction mixture is cooled and thecorresponding hydrated, pharmaceutically acceptable acid addition saltof piperidine derivatives of the formula (I) and (II) is recovered fromthe reaction zone by, for example filtration. Alternatively, theappropriate anhydrous, pharmaceutically acceptable acid addition salt ofpiperidine derivatives of the formula (I) and (II) is treated with avolume of water or a suitable water/organic solvent mixture which issufficient to cause dissolution and the water or water/organic solventis partially or completely evaporated to a volume which inducescrystallization of the hydrated, pharmaceutically acceptable acidaddition salts of piperidine derivatives of the formula (I) and (II).Suitable solvents for use in the above recrystallization are water,acetone/water, ethanol/water, methyl ethyl ketone/aqueous methanol,methyl ethyl ketone/water and the like.

[0066] The pseudomorphic forms of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Forms II and IV) may beprepared by a variety of methods as detailed below.

[0067] Ethyl Ester/Ketone to Form II

[0068] Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form IV) may be prepared fromethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate, hydrochloride or free base as described abovefor the general preparation of the hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) fromthe corresponding compound of the formula (II) wherein R₃ is —COOalkyl,but rapdily adding water over a period of time ranging from 1 minute to45 minutes at a temperature range of about −20° C. to 50° C. toprecipitate the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II).

[0069] Ethyl Ester/Ketone to Form IV

[0070] Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form IV) may be prepared fromethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate, hydrochloride or free base as described abovefor the general preparation of the hydrated, pharmaceutically acceptableacid addition salts of piperidine derivatives of the formula (I) fromthe corresponding compound of the formula (II) wherein R₃ is —COOalkyl,but slowly adding water over a period of time ranging from about 30minutes to 24 hours and at a temperature range of about 0° C. to 50° C.,optionally with seeding, to precipitate the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form IV).

[0071] Form I to Form II

[0072] Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II) may be prepared fromanhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) by subjectinghydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form II) to an aqueousrecrystallization as defined above.

[0073] Starting materials for use in the present invention are readilyavailable to one of ordinary skill in the art. For example, ethyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate, hydrochloride is described in U.S. Pat. No.4,254,129, Mar. 3, 1981.

[0074] The following examples present typical processes for preparingthe anhydrous and hydrated, pharmaceutically acceptable acid additionsalts of piperidine derivatives of the formula (I) and (II), polymorphsand pseudomorphs therof. These examples are understood to beillustrative only and are not intended to limit the scope of the presentinvention in any way. As used herein, the following terms have theindicated meanings: “g” refers to grams; “mol” refers to mole; “mmol”refers to millimoles; “mL” refers to milliliters; “bp” refers to boilingpoint; “mp” refers to melting point; “° C.” refers to degrees Celsius;“mm Hg” refers to millimeters of mercury; “μL” refers to microliters;“pg” refers to micrograms; and “μM” refers to micromolar.

[0075] Differential Scanning Calorimetry analysis were performed using aTA 2910 DSC with open aluminum pans. The samples were heated to 240° C.at 5° C./minute with a 50 mL/minute nitrogen purge.

[0076] X-Ray Powder Diffraction analyses were performed as follows:

[0077] The samples were loaded into a quartz (zero scatter) sampleholder for the XRPD pattern measurement. The XRPD patterns were measuredusing a powder diffractometer equipped with a Co X-ray tube source,primary beam monochromator, and position sensitive detector (PSD). Theincident beam was collimated using a 1° divergence slit. The active areaon the PSD subtended approximately 5°2. The source was operated at 35 kVand 30 mA and the sample was illuminated with Co ₁ radiation. XRPD datawere collected from 5 to 55° 2 at a rate of 0.25° 2/minute and a stepwidth of 0.02° 2. The XRPD patterns were measured without the additionof an internal calibrant.

[0078] Peak positions and intensities for the most prominent featureswere measured using a double-derivative peak picking method. X-ray peakswith I/I_(o) greater than 20% were reported. The cutoff was chosenarbitrarily. The intensities are rounded to the nearest 5%. Certainpeaks appear sensitive to preferred orientation that is caused bychanges in crystallite morphology. This results in large changes in theI/I_(o) value.

EXAMPLE 1 Preparation of Form II4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride

[0079] Method A

[0080] Mix ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate, hydrochloride (101.92 g, 0.1807 mol) andmethanol (510 mL) and stir. Rapidly add 50% sodium hydroxide (72.27 g,0.903 mol) and wash in with water (61 mL). Heat to reflux for 2 hours,allow to cool to 35° C. and treat with sodium borohydride (3.42 g,0.0903 mol). Add water (100 mL) and maintain at 35° C. for 10 hours. Add37% hydrochloric acid (53.0 g) to adjust pH to 11.5. Add acetone (26.5mL) and water (102 mL). Hold at 35° C. for 2 hours and adjust to pH 2.5with 37% hydrochloric acid (44.69 g). Dilute with water (408 mL), coolto −15° C., stir for 1.5 hours and collect the precipitate by vacuumfiltration. Wash the filtercake with deionized water (3×100 mL) andvacuum dry to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (97.10 g).

[0081] Method B

[0082] Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate, hydrochloride (60.01 g, 0.106 mol) in a 1-Lthree necked round-bottom flask and fit the flask with a mechanicalstirrer, a Claisen head, a thermometer and a reflux condenser with anitrogen bubbler on top. Add methanol (300 mL) and turn the stirrer on.Dilute the slurry with water (60 mL) and heat to 52-54° C. over 15-20minutes. Hold at 52° C. for 2 hours and then add 50% sodium hydroxide(42.54 g, 0.532 mol). Heat at 73° C. for approximately 1 hour, 45minutes, cool to less than 35° C. using a water bath and then add sodiumborohydride (2.02 g, 0.0534 mol). Stir overnight at 35° C., treat withacetone (15.5 mL) and stir for 2 hours at 35° C. Acidify the mixture toa pH of 1.85 with 28% hydrochloric acid (75.72 g), dilute with water(282 mL), stir for about 30 minutes and cool over about 2 hours to −15°C. Filter the solids off and wash with water (2×75 mL) and ethyl acetate(2×75 mL). Vacuum dry the solid and allow to stand for 2 days to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (57.97 g,91.5%) as a fine powder.

[0083] Method C

[0084] Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate (56.12 g, 0.1064 mol) in a 1-L three neckedround-bottom flask and fit the flask with a mechanical stirrer, aClaisen head, a thermometer and a reflux condenser with a nitrogenbubbler on top. Add methanol (300 mL) and turn the stirrer on. Dilutethe slurry with water (60 mL) and heat to reflux using a heating mantlecontrolled by a Therm-O-Watch. When the mixture reaches about 35° C.,treat with 50% sodium hydroxide (34.05 g, 0.4256 mol) and rinse in withwater (42 mL). Stir at reflux for 2 hours, 15 minutes, cool over 1 hourto 35° C. and then treat with sodium borohydride (2.02 g, 0.0534 mol).Stir for 7.5 hours and allow to stand at room temperature withoutstirring for 1.75 days. Warm the mixture to 35° C. and quench withacetone (15.5 mL, 0.21 mol) and stir for 2 hours. Add water (60 mL) andadjust the pH to 2.5 with 32% hydrochloric acid (65.22 g). Cool to 40°C. and rinse the pH probe with water (25 mL). Add water over about 30minutes (192 mL), hold the temperature at 33° C. for 10 minutes and adda few seed crystals. Cool the slurry to −12° C. over about 45 minutesand isolate the solid by filtration (586.2 g). Wash with water (2×100mL) and then with ethyl acetate (100 mL, prechilled to about −10° C.).Vacuum dry overnight (1 mmHg, 50° C.) to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (58.86 g,98%) as a white solid.

EXAMPLE 2 Preparation of Form IV4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form IV)

[0085] Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate (56.12 g, 0.1064 mol) in a 1-L three neckedround-bottom flask and fit the flask with a mechanical stirrer, aClaisen head, a thermometer and a reflux condenser with a nitrogenbubbler on top. Add methanol (300 mL) and turn the stirrer on. Dilutethe slurry with water (60 mL) and heat to reflux using a heating mantlecontrolled by a Therm-O-Watch. When the mixture reaches about 35° C.,treat with 50% sodium hydroxide (34.05 g, 0.4256 mol) and rinse in withwater (42 mL). Stir at reflux for 2 hours, 15 minutes, cool over 1 hourto 35° C. and then treat with sodium borohydride (2.02 g, 0.0534 mol).Stir for 7.5 hours and allow to stand at room temperature withoutstirring for 1.75 days. Warm the mixture to 35° C. and quench withacetone (15.5 mL, 0.21 mol) and stir for 2 hours. Add water (60 mL) andadjust the pH to 2.5 with 32% hydrochloric acid (65.22 g). Cool to 40°C. and rinse the pH probe with water (25 mL). Hold the temperature at33° C. for 10 minutes, add a few seed crystals and add water over about4 hours (192 mL) at 35° C. Cool the slurry to −12° C. over about 45minutes and isolate the solid by filtration (586.2 g). Wash with water(2×100 mL) and then with ethyl acetate (100 mL, prechilled to about −10°C.). Vacuum dry overnight (1 mmHg, 50° C.) to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV); mp 115-116°C. (dec). TABLE 5 D-Space, Angstroms Intensity, I/I_(o), % 10.38  606.97 45 6.41 50 5.55 30 5.32 100  5.23 55 5.11 35 4.98 25 4.64 30 4.3235 4.28 75 4.12 50 4.02 45 3.83 60 3.65 20 3.51 55 3.46 25 2.83 20

EXAMPLE 3 Conversion of Form II to Form I4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I)

[0086] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (20.0 g,0.0355 mol) with deionized water (2 g) and add acetone (60 mL) in smallportions over several minutes with stirring. Filter through filter aidand wash the filter cake with acetone (30 mL). Wash the filtercake withacetone (22 mL), reflux filtrate and then slowly add ethyl acetate (32mL over 15 minutes) keeping the mixture at reflux. Reflux for 10minutes, then slowly add additional ethyl acetate (23 mL over 10minutes) and reflux for an additional 15 minutes. Add additional ethylacetate (60 mL over 5-10 minutes) and continue refluxing for 15 minutes.Cool to approximately 8° C. in an ice bath, filter the solid and washwith ethyl acetate (85 mL). Vacuum dry at 55° C. for 1.5 hours to givethe title compound (18.16 g, 95%).

EXAMPLE 4 Conversion of Form II to Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride

[0087] Method A:

[0088] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (5.00 g,0.0083 mol) with methylethyl ketone (130 mL). Slowly add water (0.4 mL),filter through filter aid and wash the filter cake with methylethylketone (20 mL). Heat to reflux and distill off 75 mL of solvent, cool to−15° C. and collect by vacuum filtration. Wash with methylethyl ketone(2×10 mL) and vacuum dry at 60° C. to give the title compound (4.33 g,97%); mp 196-198° C.

[0089] Method B:

[0090] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (1.4 g) withacetone (60 mL) and heat to reflux. Reduce the volume to approximately35 mL to remove all water which boils off as an azeotrope(88/12:acetone/water). Cool the solution and collect the title compoundas a crystalline solid.

[0091] Method C:

[0092] Mix4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (53.88 g,0.100 mol) and add water (4.79 g) and methyl ethyl ketone (240 mL). Stiruntil the solid is slurried up and add additional methyl ethyl ketone(1) Stir for 0.5 hours, filter through a pad of filter aid, wash thefiltercake with methyl ethyl ketone (100 mL) and transfer the filtrateand wash to a 2 L, 3-necked flask fitted with a thermometer, mechanicalstirrer and distillation head. Distill off a total of 721 mL of methylethyl ketone, cool and stir over 1 hour to 40° C. Cool to −15° C. andhold for 10 minutes. Collect the solid by vacuum filtration and wash thefiltercake with methyl ethyl ketone (2×65 mL) and vacuum dry at 55° C.overnight to give the title compound (52.76 g, 97.9%); mp 197.5-200° C.

[0093] Method D:

[0094] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (40.0 g,0.0696 mol, assayed at 93.6% purity, having 0.89 g water present and35.1 g, 0.0575 mol, assayed at 88.0% purity, having 2.47 g waterpresent) with water (8.30 g; the amount calculated to bring the weightof water present to 17% of the anhydrous weight of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate, taking into accountthe water in the hydrated salt). Add methyl ethyl ketone (approximately500 mL) and stir until most of the solids dissolve. Add additionalmethyl ethyl ketone (700 mL) in portions over approximately 10 minutesand continue stirring for ½ hour. Filter through a thin pad of filteraid, wash the filtercake and flask with additional methyl ethyl ketone(100 mL) and transfer to a boiling flask fitted with a thermometer,mechanical stirrer, heating mantle, a 12-plate Oldershaw(vacuum-jacketed) distillation column and a distillation head with thecapability of regulating the reflux ratio in a rough fashion, washing inwith additional methyl ethyl ketone (100 mL). Distill off 450 mL ofsolvent, cool to −15° C. and filter the solid. Wash with methyl ethylketone (2×100 mL) and dry to give the title compound (68.3 g, 99.9%); mp197-199° C.

[0095] Method E

[0096] Bring methyl ethyl ketone (4 mL) to a boil and add4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (500 mg). Decant the top layerand add methyl ethyl ketone (3 mL) to the aqeuous layer. Boil thesolution until the temperature reached 79° C., reduce the volume by 25%,remove from heat and cover with aluminum toil. Allow the solution tocool, filter the resulting crystals and air dry to give the titlecompound.

EXAMPLE 5 Conversion of Form I to Form II4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate

[0097] Method A

[0098] Treat4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) (2.0 g) with ethanol(4 mL) and deionized water (20 mL). Heat at 80° C. until a solution isformed and then stir at room temperature for 23 hours. Filter theresulting slurry, wash with water (2×10 mL) and dry under vacuum at 35°C. overnight to give the title compound (1.88 g); mp 100-105° C. TABLE 6D-Space, Angstroms Intensity, I/I_(o), % 11.41  20 7.98 20 7.83 45 6.5845 6.42 60 5.66 20 5.52 45 5.39 30 5.23 65 5.14 45 4.86 65 4.72 100 4.45 65 4.40 45 4.32 45 4.18 45 4.06 65 4.02 55 3.85 25 3.79 75 3.74 953.61 80 3.56 25 3.47 65 3.41 20 2.74 20

[0099] Method B

[0100] Mix water (35.5 mL), methanol (26.3 mL) and sodium chloride (2.59g). Add 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I) (4.77 g). Heat toreflux on a steam bath until dissolution and cool to −10° C. Filter theresulting solid, wash with water (2×25 mL) and vacuum dry overnight togive the title compound (4.80 g).

EXAMPLE 6 Conversion of Form II into Form III4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form III)

[0101] Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form II) (55.56 g,0.0929 mol having 10% water) in a pressure bottle along with water (2.96g) and acetone (38.1 g). Seal the bottle tightly and heat toapproximately 80° C. Cool to about 50° C., filter through filter aid ina coarse sintered glass funnel and dilute with acetone (90 g). Transferto a 1 L flask fitted with a mechanical stirrer, thermometer and areflux condenser. Heat the mixture to reflux and allow to cool and stirover the weekend. Cool to −15° C. and filter on a coarse sintered glassfunnel, wash with ethyl acetate (2×50 mL) and vacuum dry at 50° C. Placea majority of the solid obtained (45.24 g) in a 500 mL three neckedflask fitted with a mechanical stirrer, thermometer and a refluxcondenser. Add acetone (240 mL) and water (4.82 g) and reflux themixture overnight. Allow the slurry to cool to 35° C. and place in anice water bath and cool to less then 5° C. Filter the solid off on acoarse sintered glass funnel, wash with ethyl acetate (50 mL) and vacuumdry at 50 C. for several hours to give the title compound as a whitecrystalline powder (43.83 g, 97%); mp 166.5-170.5° C. TABLE 7 D-Space,Angstroms Intensity, I/I_(o), % 8.95 95 4.99 20 4.88 100  4.75 35 4.5725 4.47 25 4.46 20 3.67 20 3.65 25

EXAMPLE 7 Conversion of Form III into Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I)

[0102] Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form III) (40.0 g as an ethylacetate wetcake-27.9 g dry basis) in a 1 L three necked flask fittedwith a mechanical stirrer, thermometer and a reflux condenser. Addacetone (240 mL) and heat the mixture to reflux for about 20 hours. Coolthe slurry to −15° C. and isolate the solids by filtration on a coarsesintered glass frit funnel. Wash with ethyl acetate (50 mL) and vacuumdry overnight to give the title compound (26.1 g, 93.7%); mp197.5-199.5° C. TABLE 8 D-Space, Angstroms Intensity, I/I_(o), % 11.75 35 7.23 35 6.24 60 5.89 40 5.02 20 4.94 30 4.83 100  4.44 30 3.93 753.83 20 3.77 85 3.71 25 3.62 30 3.32 25 3.31 20

EXAMPLE 8 Conversion of Form IV into Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride (Form I)

[0103] Place4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV) (54.35 g,0.0970 mol, having 4% water present) in a pressure bottle along withwater (4.16 g) and acetone (38.1 g). Seal the bottle tightly and heat toapproximately 80° C. Cool to less then 60° C., filter through filter aidin a coarse sintered glass funnel and rinse the filter cake with acetone(32.4 g). Place acetone (215 g) in a 1 L three necked flask fitted witha mechanical stirrer, thermometer, a reflux condenser and containing asmall amount of Form I crystals and heat to reflux. Add a portion of theacetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV) (47.65 g) tothe refluxing acetone over about 10 minutes. Slowly add ethyl acetate(157.5 g) over 45 minutes then add the remaining portion of theacetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride hydrate (Form IV), rinsed inwith about 20 mL of acetone. Add additional ethyl acetate (157.5 g) over45 minutes to 1 hour, maintaining the slurry at reflux. Stir for 15minutes, cool to −15° C. and vacuum filter the white solid on a 350 mLcoarse sintered glass funnel. Wash the solids with ethyl acetate (2×50mL) and vacuum dry overnight to give the title compound (50.36 g, 97%);mp 198-199.5° C. TABLE 9 D-Space, Angstroms Intensity, I/I_(o), % 14.89 20 11.85  20 7.30 20 6.28 70 5.91 25 5.55 20 5.05 25 4.96 55 4.85 100 4.57 45 4.45 55 3.94 45 3.89 20 3.84 20 3.78 60 3.72 35 3.63 20 3.07 203.04 20 2.45 20

[0104] The polymorphic and pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compounds of this inventionare useful as antihistamines, antiallergy agents and bronchodilators andmay be administered alone or with suitable pharmaceutical carriers, andcan be in solid or liquid form such as, tablets, capsules, powders,solutions, suspensions or emulsions.

[0105] The polymorphic and pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compounds of this inventioncan be administered orally, parenterally, for example, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation or by application to mucous membranes, such as, that of thenose, throat and bronchial tubes, for example, in an aerosol spraycontaining small particles of a compound of this invention in a spray ordry powder form.

[0106] The quantity of polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compound administered willvary depending on the patient and the mode of administration and can beany effective amount. The quantity of polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compound administered may varyover a wide range to provide in a unit dosage an effective amount offrom about 0.01 to 20 mg/kg of body weight of the patient per day toachieve the desired effect. For example, the desired antihistamine,antiallergy and bronchodilator effects can be obtained by consumption ofa unit dosage form such as a tablet containing 1 to 500 mg of apolymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compound of this inventiontaken 1 to 4 times daily.

[0107] The solid unit dosage forms can be of the conventional type.Thus, the solid form can be a capsule which can be the ordinary gelatintype containing a polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compound of this invention anda carrier, for example, lubricants and inert fillers such as lactose,sucrose or cornstarch. In another embodiment the polymorphic orpseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compound is tableted withconventional tablet bases such as lactose, sucrose or cornstarch orgelatin, disintegrating agents such as cornstarch, potato starch oralginic acid, and a lubricant such as stearic acid or magnesiumstearate.

[0108] The polymorphic or pseudomorphic4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride compounds of this inventionmay also be administered in injectable dosages by solution or suspensionof the compounds in a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid such as water andoils, with or without the addition of a surfactant and otherpharmaceutically acceptable adjuvants. Illustrative of oils there can bementioned those of petroleum, animal, vegatable or synthetic origin, forexample, peanut oil, soybean oil or mineral oil. In general, water,saline, aqueous dextrose and related sugar solutions and glycols such aspropylene glycol or polyethylene glycol are preferred liquid carriers,particularly for injectable solutions.

[0109] For use as aerosols the compounds of this invention in solutionor suspension may be packaged in a pressurized aerosol containertogether with suitable propellants, for example, hydrocarbon propellantssuch as, propane, butane or isobutane with the usual adjuvants as may beadministered in a non-pressurized form such as in a nebulizer oratomizer.

[0110] The term patient as used herein is taken to mean warm bloodedanimals, birds, mammals, for example, humans, cats, dogs, horses, sheep,bovine cows, pigs, lambs, rats, mice and guinea pigs.

What is claimed is:
 1. A process for preparing a compound of the formula

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; n is an integer of from 1 to 5; R₃ is —CH₂OH, —COOHor —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms andis straight or branched; W is —CH(OH)— or —C(═O)—; A is hydrogen orhydroxy; Y is a pharmaceutically acceptable acid; and the individualoptical isomers thereof, comprising subjecting a compound of the formula

and the individual optical isomers thereof, wherein R₁, R₂, R₃, n, W, Aand Y are defined above and X is a number ranging essentially from 0.10to 5 to an azeotropic distillation.
 2. A process for preparing acompound of the formula

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; n is an integer of from 1 to 5; R₃ is —CH₂OH, —COOHor —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms andis straight or branched; W is —CH(OH)— or —C(═O)—; A is hydrogen orhydroxy; Y is a pharmaceutically acceptable acid; and the individualoptical isomers thereof, comprising subjecting a compound of the formula

and the individual optical isomers thereof, wherein R₁, R₂, R₃, n, W, Aand Y are defined above and X is a number ranging essentially from 0.10to 5 to a water-minimizing recrystallization.
 3. A process for preparinga compound of the formula

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; n is an integer of from 1 to 5; R₃ is —CH₂OH, —COOHor —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms andis straight or branched; W is —CH(OH)— or —C(═O)—; A is hydrogen orhydroxy; Y is a pharmaceutically acceptable acid; X is a number rangingessentially from 0.1 to 5; and the individual optical isomers thereof,comprising subjecting a compound of the formula

and the individual optical isomers thereof wherein R₁, R₂, R₃, n, A, Wand Y are as defined above, to an aqueous recrystallization.
 4. Aprocess for preparing a compound of the formula

and the individual optical isomers thereof, wherein Y is apharmaceutically acceptable acid, comprising subjecting a compound ofthe formula

wherein Y is as defined above and X is a number ranging essentially from0.10 to 5 to an azeotropic distillation.
 5. A process for preparing acompound of the formula

and the individual optical isomers thereof, wherein Y is apharmaceutically acceptable acid, comprising subjecting a compound ofthe formula

wherein Y is as defined above and X is a number ranging essentially from0.10 to 5 to a water-minimizing recrystallization.
 6. A process forpreparing a compound of the formula

and the individual optical isomers thereof, wherein Y is apharmaceutically acceptable acid and X is a number ranging essentiallyfrom 0.10 to 5, comprising subjecting a compound of the formula

wherein Y is as defined above to an aqueous recrystallization.
 7. Aprocess according to claim 4, claim 5 or claim 6 wherein Y is HCl.
 8. Aprocess according to claim 7 wherein x is a number ranging from 1 to 4.9. A process according to claim 8 wherein x is a number ranging from 2to
 3. 10. A compound of the formula

and the individual optical isomers thereof, formed by the processcomprising the steps of: a) treating a compound of the formula

 wherein X is a number ranging from 0.1 to 5 and the individual opticalisomers thereof, with a suitable solvent or solvent mixture; b) heatingthe mixture to a suitable temperature; and c) cooling the mixture tocomplete crystallization.
 11. A compound of the formula

and the individual optical isomers thereof, formed by the processcomprising the steps of: a) treating a compound of the formula

 wherein X is a number ranging from 0.1 to 5 and the individual opticalisomers thereof, with a suitable anhydrous solvent or solvent mixture inan amount sufficient to cause dissolution; b) heating the mixture to asuitable temperature. c) adding an additional volume of a suitableanhydrous solvent or solvent mixture in a quantity sufficient toinitiate crystallization; and d) cooling the reaction mixture tocomplete crystallization.
 12. A compound of the formula

wherein X is a number ranging from 0.1 to 5 and the individual opticalisomers thereof, formed by the process comprising the steps of: a)treating a compound of the formula

 and the individual optical isomers thereof with a suitable solvent; b)heating the mixture to a suitable temperature; and c) cooling themixture to initiate crystallization.
 13. Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride.
 14. Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride.
 15. Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride.
 16. Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride.
 17. A pharmaceuticalcomposition comprising an effective antiallergic amount of a compound ofclaim 13 in admixture or otherwise in association with an inert carrier.18. A pharmaceutical composition comprising an effective antiallergicamount of a compound of claim 14 in admixture or otherwise inassociation with an inert carrier.
 19. A pharmaceutical compositioncomprising an effective antiallergic amount of a compound of claim 15 inadmixture or otherwise in association with an inert carrier.
 20. Apharmaceutical composition comprising an effective antiallergic amountof a compound of claim 16 in admixture or otherwise in association withan inert carrier.
 21. A method of treating allergic reactions in apatient in need thereof which comprises administering to said patient ananti-allergically effective amount of a compound of claim
 13. 22. Amethod of treating allergic reactions in a patient in need thereof whichcomprises administering to said patient an anti-allergically effectiveamount of a compound of claim
 14. 23. A method of treating allergicreactions in a patient in need thereof which comprises administering tosaid patient an anti-allergically effective amount of a compound ofclaim
 15. 24. A method of treating allergic reactions in a patient inneed thereof which comprises administering to said patient ananti-allergically effective amount of a compound of claim
 16. 25. Aprocess for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises subjectingForm II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride to a water-minimizingrecrystallization.
 26. A process according to claim 25 wherein suitableanhydrous solvents or solvent mixtures which are sufficient to causedissolution are acetone and water and a suitable anhydrous antisolventis ethyl acetate.
 27. A process for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises subjectingForm II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride to an azeotropic distillation.28. A process according to claim 27 wherein suitable solvents or solventmixtures which are sufficient to cause dissolution are methanol,acetone/water and methyl ethyl ketone/water and a suitable anhydrousantisolvent is methyl ethyl ketone.
 29. A process for preparing the FormI anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-dimethylbenzeneaceticacid hydrochloride which comprises subjecting Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl],-dimethylbenzeneacetic acid hydrochloride to a crystal digestion.
 30. Aprocess for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises subjectingForm IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride to a water-minimizingrecrystallization.
 31. A process according to claim 30 wherein suitableanhydrous solvents or solvent mixtures which are sufficient to causedissolution are acetone and water and a suitable anhydrous antisolventis ethyl acetate.
 32. A process for preparing the Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises subjectingForm IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride to an azeotropic distillation.33. A process according to claim 32 wherein suitable solvents or solventmixtures which are sufficient to cause dissolution are methanol,acetone/water and methyl ethyl ketone/water and a suitable anhydrousantisolvent is methyl ethyl ketone.
 34. A process for preparing the FormII hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises: a) reactingethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate hydrochloride with an appropriate reducing agentin a suitable solvent; b) acidifying with hydrochloric acid; and c)adding water over a period of time ranging from 1 minute to 45 minutesat a temperature range of about −20° C. to 50° C.
 35. A processaccording to claim 34 wherein the water is added over a period of timeranging from 10 minutes to 30 minutes at a temperature range of about 0°C. to 40° C.
 36. A process according to claim 35 wherein the water isadded over a period of time ranging from 10 minutes to 30 minutes at atemperature range of about 20° C. to 40° C.
 37. A process for preparingthe Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises: a) reactingethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate with an appropriate reducing agent in a suitablesolvent; b) acidifying with hydrochloric acid; and c) adding water overa period of time ranging from 1 minute to 45 minutes at a temperaturerange of about −20° C. to 50° C.
 38. A process according to claim 37wherein the water is added over a period of time ranging from 10 minutesto 30 minutes at a temperature range of about 0° C. to 40° C.
 39. Aprocess according to claim 38 wherein the water is added over a periodof time ranging from 10 minutes to 30 minutes at a temperature range ofabout 20° C. to 40° C.
 40. A process for preparing the Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises subjectingForm I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl],-dimethylbenzeneacetic acid hydrochloride to an aqueousrecrystallization.
 41. A process for preparing the Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises subjectingForm II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride to a water-minimizingrecrystallization.
 42. A process for preparing the Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises: a) reactingethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate hydrochloride with an appropriate reducing agentin a suitable solvent; b) acidifying with hydrochloric acid; and c)adding water over a period of time ranging from 30 minutes to 24 hoursat a temperature range of about 0° C. to 50° C.
 43. A process accordingto claim 42 wherein the water is added over a period of time rangingfrom 1 hour to 12 hours at a temperature range of about 10° C. to 40° C.44. A process according to claim 43 wherein the water is added over aperiod of time ranging from 2 hours to 8 hours at a temperature range ofabout 20° C. to 40° C.
 45. A process for preparing the Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,-dimethylbenzeneacetic acid hydrochloride which comprises: a) reactingethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate with an appropriate reducing agent in a suitablesolvent; b) acidifying with hydrochloric acid; and c) adding water overa period of time ranging from 30 minutes to 24 hours at a temperaturerange of about 0° C. to 50° C.
 46. A process according to claim 45wherein the water is added over a period of time ranging from 1 hour to12 hours at a temperature range of about 10° C. to 40° C.
 47. A processaccording to claim 46 wherein the water is added over a period of timeranging from 2 hours to 8 hours at a temperature range of about 20° C.to 40° C.